2-55667112-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033109.5(PNPT1):c.1074-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,570,290 control chromosomes in the GnomAD database, including 189,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15891 hom., cov: 32)
  • Exomes 𝑓: 0.49 (173284 hom.)
• Consequence: PNPT1 NM_033109.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.247

Genes affected

PNPT1 (HGNC:23166): (polyribonucleotide nucleotidyltransferase 1) The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-55667112-T-C is Benign according to our data. Variant chr2-55667112-T-C is described in ClinVar as [Benign]. Clinvar id is 138735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-55667112-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPT1	NM_033109.5	c.1074-19A>G		intron_variant		ENST00000447944.7
PNPT1	XM_005264629.3	c.834-19A>G		intron_variant
PNPT1	XM_017005172.2	c.834-19A>G		intron_variant
PNPT1	XM_047446161.1	c.1074-19A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPT1	ENST00000447944.7	c.1074-19A>G		intron_variant		1	NM_033109.5	P1
PNPT1	ENST00000260604.8	c.*629-19A>G		intron_variant, NMD_transcript_variant		5
PNPT1	ENST00000415374.5	c.1074-19A>G		intron_variant, NMD_transcript_variant		5
PNPT1	ENST00000415489.1	c.148-19A>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67525 AN: 151930 Hom.: 15896 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.471

GnomAD3 exomes AF: 0.440 AC: 108601 AN: 246766 Hom.: 25934 AF XY: 0.438 AC XY: 58457 AN XY: 133474

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.269

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.488

GnomAD4 exome AF: 0.486 AC: 689819 AN: 1418242 Hom.: 173284 Cov.: 24 AF XY: 0.481 AC XY: 340393 AN XY: 708056

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.446

Gnomad4 ASJ exome AF: 0.481

Gnomad4 EAS exome AF: 0.165

Gnomad4 SAS exome AF: 0.271

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.444 AC: 67539 AN: 152048 Hom.: 15891 Cov.: 32 AF XY: 0.442 AC XY: 32870 AN XY: 74336

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.468

Alfa AF: 0.453 Hom.: 7363

Bravo AF: 0.433

Asia WGS AF: 0.248 AC: 864 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -

Combined oxidative phosphorylation defect type 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Autosomal recessive nonsyndromic hearing loss 70 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.14
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782637; hg19: chr2-55894247; COSMIC: COSV53179089;